Thromboembolic diseases are a leading cause of morbidity and mortality in the developed world and are rapidly emerging in the developing world. Currently commercialized antithrombotic agents are usually associated with the side effect of causing bleeding. In spite of the introduction of new oral anticoagulants into the clinic in the last few years (e.g., dabigatran etexilate, rivaroxaban, edoxaban for example) there remain unmet needs.
Factor XI inhibition has been identified as an attractive target for drug development because mice or humans with abnormally low FXI levels appear to be protected from thrombosis. An antisense oligonucleotide to FXI named FXI-ASO (ISIS416858) is under clinical development (Büller et al., 2014) and was determined to be superior in preventing venous thromboembolism in patients undergoing total knee replacement than the standard of care. Importantly, the study demonstrated that the antisense oligonucleotide did not promote bleeding in orthopedic surgery, a major challenge with any antithrombic agent. However, it took five weeks for the antisense oligonucleotide FXI-ASO (ISIS416858) to reduce FXI levels by 10 to 20% of normal (e.g. pre-treatment) levels and FXI levels were also slow to recover after the drug was stopped (Buller et al., 2014).
It would be highly desirable to be provided with a specific inhibitor of Factor XIa (FXIa), e.g., a compound which would specifically bind to (and inhibit the biological activity of) Factor XIa. It would also be desirable to be provided with a FXIa inhibitor, which would have a rapid onset of action and/or a short duration of action for treating and/or preventing thrombosis. It would further be highly desirable to be provided with a FXIa inhibitor which would exhibit little to no immunogenicity (upon administration to the intended recipient).